Patients with the pathologic diagnosis of Alzheimer's disease (AD) commonly (approximately 30 to 60%) have concomitant Lewy body (LB) formation as detected with o_-synuclein immunohistochemical analysis of extra-nigral sites. These patients with AD/LB, along with a much less common dementia characterized by LB formation alone, are currently classified as having Dementia with Lewy Bodies (DLB). There is substantial clinical and pathologic heterogeneity among patients with DLB, thwarting efforts to understand fully the significance of distinguishing AD from DLB and strongly suggesting further distinct subgroups within what is currently called DLB. Here we propose to test the hypothesis that DLB differs from AD at clinical, pathologic, molecular genetic, and biochemical levels, and that these same criteria may be used to discem multiple distinct subgroups of DLB. We will expand an already functioning cooperative study among five Alzheimer Disease Centers (ADC) across the United States: Oregon Health & Science University, University of California at San Diego, University of Pennsylvania, University of Pittsburgh, and University of Washington. We propose to collect clinical and neuropathological data as well as banked tissue from approximately 100 age-matched controls, 250 patients with AD, and 250 patients with DLB. We estimate collection of 20, 50, and 50, respectively, additional cases for each year of this project. Using the robust design of patient data and material from five separate ADCs and biostatistical support from the National Alzheimer's Coordinating Center (NACC), we will test our hypothesis by pursuing these specific aims: to distinguish controls, AD, and DLB, and as well as DLB subgroups by determining (1) clinical and pathological features, (2) characteristics of candidate genes, (3) quantitative differences in oxidative damage, and (4) alterations in both soluble and insoluble forms of tan, A[3, and (z-synuclein. Successful completion of this project will solidify our understanding of DLB and provide a foundation for future clinical and molecular studies of this second most common form of dementia. Specifically, this project will establish a National DLB Resource, including a database of clinico-pathologic data, as well as an inventory of DNA samples and frozen brain tissue. This resource will be made available for future investigations of DLB.